6. PROJECT SUMMARY/ABSTRACT The goal of this proposal is to obtain funding for a state-of-the-art high resolution high speed MALDI TOF/TOF mass spectrometer to be housed in the UW-Madison School of Pharmacy Analytical Instrumentation Center (AIC) MS Facility. This cutting-edge instrument will offer several unique features: (1) Un-paralleled spatial resolution for tissue imaging compared to any of our existing MALDI MSI platforms; (2) Fast data acquisition speed which is essential for imaging of larger tissue areas with enhanced spatial resolution and for high throughput screening; (3) Enhanced sensitivity for both MS and MS/MS; (4) Capability of MS/MS at mass range up to 8 kDa and unlimited mass range for MS measurements that are useful for in situ protein identification and mapping posttranslational modifications. Finally, the robust ion source design enabled less frequent cleaning and ability to acquire both MS and MS/MS images from the same tissue section. This new instrument will provide advanced MS capabilities to support the research of 21 highly productive NIH-funded investigators with 46 ongoing projects. The access to this state-of-the-art high performance mass spectrometer will help to address multiple levels of human health-related research including, (1) Enhanced (neuro)peptidomics with increased chemical and spatial information; (2) Comparative in situ tissue proteomics for biomarker discovery and disease mechanistic investigation; (3) Small molecule metabolite and lipid profiling and tissue imaging in various disease model systems; (4) MSI approach to investigate drug delivery and metabolite distribution; (5) Natural product discovery and characterization; and (6) MALDI MSI of metabolites and peptides in plants. Progress on this broad array of projects will be catalyzed by the effective usage of the new instrument through close cooperation among the user groups and Dr. Li, a highly productive faculty member with more than 25 years of experience in biological mass spectrometry, and Dr. Scarlett, the UW-Madison Pharmacy-MS Facility Director.